Friday, December 28, 2007

Drug Combo Extends Progression-Free Survival in Breast Cancer

By Todd Neale
INDIANAPOLIS, Dec. 27 -- Adding bevacizumab (Avastin) to paclitaxel (Taxol) prolonged progression-free survival as initial treatment for metastatic breast cancer, researchers said.
request to recommend approval of bevacizumab for treatment of metastatic breast cancer.
Patients receiving the combination had a median progression-free survival of 11.8 months compared with 5.9 months with paclitaxel alone (hazard ratio for progression: 0.60, P<0.001), Kathy Miller, M.D., of the Indiana University Cancer Center here, and colleagues, reported in the Dec. 27 issue of the New England Journal of Medicine.
But overall survival, which Richard Pazdur, M.D., head of oncology drugs at the FDA's Center for Drug Evaluation and Research, believes to be the more important endpoint, did not differ significantly between the two groups (median, 26.7 months for the combination group versus 25.2 months for the paclitaxel-alone group, HR: 0.88, P=0.16).
Citing the lack of benefit in overall survival and added toxicities associated with the drug, the FDA's Oncology Drugs Advisory Committee rejected Genentech's request to recommend approval of bevacizumab for treatment of metastatic breast cancer earlier this month.In this open-label, randomized, phase 3 trial, Dr. Miller and colleagues recruited 722 women with breast cancer -- 614 with HER2-negative disease -- from December 2001 through May 2004. Patients were not allowed to participate in the trial if they had received prior cytotoxic therapy for metastatic disease or if they suffered from clinically significant cardiovascular disease.
The researchers assigned 368 patients to receive 90 mg of paclitaxel per square meter of body-surface area on days one, eight, and 15 of a 28-day cycle. The remaining 354 patients received the same treatment, plus 10 mg IV of bevacizumab per kilogram of body weight on days one and 15.
The two groups of patients were similar except that there were more patients with visceral involvement and measurable disease in the paclitaxel-alone group than in the combination group.
At study end, paclitaxel plus bevacizumab increased the objective response rate in all patients (36.9% versus 21.2%, P<0.001) and in the subgroup of patients with measurable disease at baseline (49.2% versus 25.2%, P<0.001) compared with paclitaxel alone.
The combination also increased the one-year survival rate for all patients (81.2% versus 73.4%, P=0.01).
In patients who had received taxane-based adjuvant therapy, the combination extended progression-free survival from three to 12 months (HR: 0.46, P<0.001).
When age was treated as a continuous variable, the effect of bevacizumab declined significantly (P=0.04) as patients grew older.
The researchers stopped collecting survival data on June 7, 2007. At that time, 483 patients had died, with the vast majority (88.8%) succumbing to progressive disease.
Toxic effects of both paclitaxel and bevacizumab led to cessation of treatment in some patients. The following adverse events were significantly more common in the combination group than in the paclitaxel-alone group: grade 3 or 4 neuropathy (23.6% versus 17.6%, P=0.03), infection (9.3% versus 2.9%, P<0.001), and fatigue (8.5% versus 4.9%, P=0.04).
Treatment was halted at least three weeks before disease progression because of adverse events in 117 (35.9%) patients in the paclitaxel-alone group and 178 (51.3%) patients in the combination group.
Patients receiving paclitaxel plus bevacizumab were also significantly more likely to have cerebrovascular ischemia (1.9% versus 0%, P=0.02) and grade 3 or 4 headaches (2.2% versus 0%, P=0.008).
A previous phase 3 study had found that the addition of bevacizumab to capecitabine increased the objective response, but neither progression-free nor overall survival (J Clin Oncol 2005; 23: 792-799).
Dr. Miller and colleagues conjectured that differences between the patient populations could account for the different results found in this recent study.
"All patients in the earlier study had received previous anthracycline and taxane therapy," they wrote, "and most (more than 85%) had received chemotherapy for metastatic disease. In contrast, 35.3% of our patients had not received any previous chemotherapy, and only 13.2% had received both an anthracycline and a taxane as adjuvant therapy."
The authors also presented the possibility that "perhaps paclitaxel is uniquely synergistic with bevacizumab."
They concluded that, "although benefit was seen across a number of clinically important subgroups, our results would be strengthened by the ability to identify patients most likely to benefit from VEGF-directed therapies."
Funding for this study came from the National Cancer Institute and Genentech, maker of bevacizumab. Genentech provided the bevacizumab for this study.
Dr. Miller reported receiving lecture fees and consulting fees for service on breast cancer advisory boards from Roche. Other co-authors reported receiving lecture or consulting fees from Genentech, Roche, GlaxoSmithKline, Bristol-Myers Squibb, and sanofi-aventis.
Primary source: New England Journal of MedicineSource reference:Miller K, "Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer" N Engl J Med 2007; 357: 2666-76.
Hypothermia Increases Blood Loss During Surgery

By Michael Smith
CLEVELAND, Dec. 27 -- Less than a degree of hypothermia is enough to significantly increase blood loss during surgery (P<0.009), researchers here said. A meta-analysis of published studies shows that the same degree of hypothermia is also enough to increase the need for transfusions significantly (P<0.027), according to Daniel Sessler, M.D., and colleagues at the Cleveland Clinic.
Add that this study -- a meta-analysis -- suggests that allowing surgical patients to have lower than normal temperatures even by less than a degree, is enough to increase blood loss and the need for transfusions. The findings clarify an area of controversy, since studies of the issue had given conflicting results, the researchers reported in the January issue of Anesthesiology.
"When all the studies were evaluated together, the results clearly show that even very mild hypothermia increases blood loss and transfusion requirements by clinically important amounts," Dr. Sessler said.
The data imply that -- except for special cases -- patients should be maintained at a normal temperature during surgery, the researchers concluded.
In a literature search, the researchers narrowed 1,800 studies down to 18 that met initial criteria; four were excluded for reporting problems. The meta-analysis was thus based on 14 studies that met preset criteria for an analysis of blood loss and 10 that met criteria for analysis of transfusion.
Studies were excluded if they were retrospective, if the core temperature was reduced to less than 34° C, if local cooling methods had been used, or if the sample size was smaller than 15.
All told, there were 1,219 patients in the blood loss studies and 985 in the transfusion studies.
The median of the mean temperatures reported for normothermic patients in the 14 blood loss studies was 36.6° C, compared to 35.6° C in the hypothermic patients.
The median temperature difference between normothermic and hypothermic groups in the studies was 0.85° C.
Analysis found:
Normothermia was associated with significantly lower blood loss. The estimated ratio of geometric means of total blood loss was 0.84, favoring a normal temperature, with a 95% confidence interval from 0.74 to 0.96, which was significant at P<0.009.
Normothermia was also associated with a reduced need for transfusion. The overall estimated relative risk was 0.78, with a 95% confidence interval from 0.63 to 0.97, which was significant at P<0.027.
In other words, the researchers said, even mild hypothermia of less than 1° C increases blood loss by about 16% and the relative risk for transfusion by about 22%.
Dr. Sessler and colleagues noted that hypothermia in the evaluated studies was "of a magnitude that is typical for unwarmed surgical patients." They added that therapeutic hypothermia would probably produce greater impairment of coagulation.
But Dr. Sessler said there are still situations where induced hypothermia is necessary.
"In occasional patients, mostly those at risk for brain injury, hypothermia is perfectly appropriate," Dr. Sessler said. "In these patients, physicians need to trade off the potential benefits and risks and choose the optimal approach for each individual."
The researchers cautioned that the study -- like all meta-analyses -- is subject to any flaws in the underlying studies. It may also be confounded, they said, by publication bias.
They also cautioned that there are several instances of meta-analyses being contradicted by large prospective randomized trials. In this case, however, it is unlikely that a prospective randomized trial could be conducted ethically, since keeping surgical patients at normal temperatures has become the standard of care.
The study was supported by the NIH and the Joseph Drown Foundation.
Dr. Sessler reported no conflicts.
Additional source: AnesthesiologySource reference: Rajagopalan S, et al "The effects of mild perioperative hypothermia on blood loss and transfusion requirement" Anesthesiology 2008; 108: 71-7. Related Article(s):
Antifibrinolytics Found to Reduce Bleeding Safely in Elective Surgery
Bereavement Associated With Early Mortality Risk

Pauline Anderson

December 21, 2007 — A new review of the literature shows that bereavement is associated with an increase in mortality risk, particularly in the first weeks or months following a loss.

A "broken heart," or the psychological stress following the loss of a loved one, along with related losses such as changes to living arrangements and economics, may increase the risk for death in the person who is mourning, the authors, led by Margaret Stroebe, MD, from the Research Institute for Psychology and Health at Utrecht University, in the Netherlands, conclude.

Further, people who have been bereaved are more likely to have physical health problems, with higher rates of disability, medication use, and hospitalization, compared with nonbereaved people, they note. However, in most cases, professional counseling does not improve outcomes for people who are grieving the loss of a loved one, but rather, most cases of uncomplicated grief will resolve without intervention, the authors conclude.

Their report is published in the December 8 issue of the Lancet.

Absolute Risk is Low

For the review, the investigators analyzed reports on bereavement published after 1997, mostly from the United States, Europe, and Australia.

Bereavement, the situation of having lost someone significant through death, according to Dr. Stroebe, is a normal life event, and most people recover emotionally and physically over the long term. "For most people, the experience, though difficult, is tolerable and abates with time. For some, however, the suffering is intense and prolonged," the authors write.

Several studies in Europe and North America have examined excess mortality in relation to bereavement, they note. One, for example, found a 3.3-fold increase in risk for suicide in men over 60 years of age who lost their wife, but no such increase in women of the same age who lost their husband.

Another report in 2006 showed that widowers had a 21% increased risk for all-cause mortality and widows a 17% increased risk. Risks were further increased in the first 30 days after bereavement. For parents losing children, a Danish study published in 2003 showed fathers and mothers have an increased risk for suicide after the death of a child, a risk that is higher with younger children and particularly high in the first 30 days after bereavement.

"The patterns are quite consistent, enabling the conclusion that the mortality of bereavement is attributable in large part to a so-called broken heart," the authors write. However, they note, "Although mortality is a drastic outcome of losing a loved one, it must be assessed in terms of the absolute number of bereaved people who die. Baseline rates are low, with, for instance, about 5% of widowers vs 3% of married men in the 55-years-and-older category dying in the first 6 months of bereavement."

Grief Distinct From Depression

The study noted that grief, defined by Dr. Stroebe as the primarily emotional reaction to the loss of a loved one through death, is a normal but complex reaction to loss, incorporating diverse psychological and physical manifestations. For most people, family, friends, religious and community groups, and various societal resources provide the necessary support. "Professional psychological intervention is generally neither justified nor effective for uncomplicated forms of grief," the authors wrote.

The authors made a distinction between grief and depression. "Growing evidence suggests that depression and grief might represent distinct, though related, clusters of reactions to bereavement," they write.

But many studies report an increase in psychiatric symptoms among the bereaved. For a few people, depression reaches clinical importance; findings of some studies suggest that 25% to 45% have mild levels of depressive symptoms and 10% to 20% show clinical levels. Bereaved people can also develop posttraumatic stress disorder (PTSD), especially following a particularly horrific death. One study found that among bereaved parents 5 years after the death of their child, 27.7% of mothers and 12.5% of fathers met diagnostic criteria for PTSD.

Complicated grief — grief that might be considered pathological due to its high intensity, long duration, or dominant symptoms, according to Dr. Stroebe, is not classified as a category of mental disorder in the Diagnostic and Statistical Manual of Mental Disorders, 4th ed (DSM-IV).

Whether it should be included is an important issue facing bereavement researchers today, she said in an email comment to Medscape Psychiatry. She noted that there are good arguments for inclusion; for example, it would enable those who most need professional help to get it. But there are also arguments against inclusion, a main one being the fear that grief will become unnecessarily "medicalized."

Links to Increased Physical Illness

The study authors also cite research showing that bereavement is linked to impaired memory, nutritional problems, work and relationship difficulties, concentration problems, and decreases in social participation. It is also associated with increased risks for physical illness. “For example, research has been done looking at how bereavement affects the immune system; leads to changes in the endocrine, autonomic nervous, and cardiovascular systems; and helps to account for increased vulnerability to external agents," the authors write.

However, many potential risk factors have been underresearched, they said. Research is only now beginning to look at the importance of certain personality traits, such as resilience. "Findings of available studies support the view that robust individuals adjust to bereavement better than people who are fragile," the authors write, adding that further research is needed on other predisposing vulnerabilities such as previous mental-health disorders and substance abuse.

Working Through Grief May Not Help

The researchers also looked at the role of support groups but raise questions about whether "grief work" is necessary. In recent decades, they write, "researchers have been critical of the generally accepted notion that so-called grief work (confronting the reality of loss and relinquishing the bond to the deceased individual) is essential for overcoming bereavement. Empirical research has shown that people who do not work through their grief frequently recover as well as, if not better than, those who do so.”

They note that to their knowledge very little research exists on the effectiveness of pharmacological and medical interventions for bereaved people.

Dr. Stroebe is currently at work on a new handbook of bereavement research. One of the areas she will touch on in her new book, she said, are remarkable developments in the examination of brain systems, including the use of functional magnetic resonance imaging of the brain, to investigate the neural circuits associated with emotion-motivation systems. Emerging research looks at neural mechanisms underlying the state of romantic rejection to see whether there are possible implications for the psychobiology of bereavement.

Lancet. 2007;370:1960-1973. Abstract

Most General Surgeons Do Not Discuss Reconstruction Before Breast Cancer Surgery

Laurie Barclay
December 26, 2007 — Only one third of patients with breast cancer surveyed reported that their general surgeons discussed breast reconstruction with them before surgery, according to the results of a study reported in the December 21 Online First issue of Cancer. When this discussion did precede surgery, it facilitated an informed surgical treatment decision-making process and increased the likelihood that women would choose a mastectomy.

"Reconstruction is rarely incorporated into the decision-making process for surgical breast cancer treatment," write Amy K. Alderman, MD, MPH, from the University of Michigan Medical Center in Ann Arbor, and colleagues. "All else being equal, the option of breast reconstruction may make mastectomy more appealing to women who strongly value breast preservation. There is virtually no information on whether knowledge of reconstruction before initial surgical treatment choice is associated with an increased propensity to receive mastectomy among women with early stage breast cancer."

Using the Detroit and Los Angeles Surveillance, Epidemiology, and End Results (SEER) cancer registries, the investigators surveyed 1844 women aged 79 years or younger with breast cancer (response rate, 77.4%). Dependent variables were yes-or-no answers to questions of whether patients had a discussion about breast reconstruction with their general surgeon, whether this discussion affected their willingness to be treated with a mastectomy, and whether the patient received a mastectomy. Independent variables were age, race, education, tumor size, tumor behavior, and presence of comorbidities. Statistical analyses included χ2 or t test, and logistic regression.

During the surgical decision-making process for their cancer, only one third of patients had a general surgeon discuss breast reconstruction with them. Younger, more educated patients with larger tumors were significantly more likely to report having this discussion with their surgeons.

Being informed of reconstructive options was associated with significantly increased willingness by patients to consider a mastectomy (odds ratio [OR], 2.06; P < .01), and having this discussion also affected actual choice of surgical treatment. Compared with patients who did not discuss reconstruction with their general surgeon, those who did were more than 4 times likely to undergo mastectomy (OR, 4.48; P <.01).

"Most general surgeons do not discuss reconstruction with their breast cancer patients before surgical treatment," the study authors write. "When it occurs, this discussion significantly impacts women's treatment choice, making many more likely to choose mastectomy. This highlights the importance of multidisciplinary care models to facilitate an informed surgical treatment decision-making process."

Limitations of the study include sample restricted to 2 metropolitan areas, limiting generalizability; self-reported outcomes possibly subject to recall bias; inability to determine whether reconstruction discussions were initiated by patients or surgeons; and retrospective design.

"Our findings suggest that the underlying paradigm of informed breast cancer treatment decision-making may need to change to include mastectomy with the option of reconstruction, especially for patients who have clinical contraindications to BCS [breast-conserving surgery], those who express a preference for treatment with mastectomy, and those who are uncertain about their treatment choice," the study authors conclude. "To achieve this shift, general surgeons should consider incorporating discussions of reconstruction or referring patients to plastic surgeons before the patient's surgical decision."

The National Cancer Institute funded this study, and cancer incidence data collection was supported by the California Department of Health Services.

Cancer. Published online December 21, 2007.

SMASH-VT Published: Ablation Reduces Incidence of Future ICD Therapy in Post-MI Patients

Michael O'Riordan
December 27, 2007 — A small, randomized study of post–myocardial infarction (MI) patients who received an implantable cardioverter defibrillator (ICD) after a first arrhythmic event has shown that substrate-based catheter ablation can be performed to reduce the incidence of future ICD therapies [1]. Compared with control patients, radiofrequency catheter ablation guided by electronanatomic mapping of the ventricular arrhythmia substrate reduced the incidence of future shocks by 73%, report investigators.

Results of the study, known as the Substrate Mapping and Ablation in Sinus Rhythm to Halt Ventricular Tachycardia (SMASH-VT) trial, which was first presented at the Heart Rhythm Society 2006 Scientific Sessions by Dr Vivek Reddy (Massachusetts General Hospital, Boston), the lead author of the study, are now published in the December 20, 2007 issue of the New England Journal of Medicine.

Although the findings leave open the future possibility that ventricular tachycardia-substrate ablation might be considered a clinical prophylactic option in post-MI patients who already have multiple ICD shocks, an editorial accompanying the published study stresses that option is still distant [2].

"Clinicians should mind the gap between the current practice and the promise of curing ventricular tachycardia with ablation techniques," writes Dr NA Mark Estes III (Tufts University School of Medicine, Boston, MA). "To bridge this gap, additional trials are needed to assess the comparative benefit of catheter ablation and antiarrhythmic drugs, to identify which subgroups of patients are most likely to benefit, to evaluate the effect of operator expertise, and to assess quality of life and cost. Until such data are available, catheter-ablation therapy should not be considered clinically indicated as prophylaxis to prevent ICD therapy."

Ablation of VT is a significant procedure

As previously reported by heartwire, the SMASH-VT investigators randomized 128 patients at three hospitals, two in Boston and one in the Czech Republic, to undergo or not undergo radiofrequency substrate ablation. The patients were required to have a history of MI and be scheduled for ICD implantation or to have had an ICD put in recently. Their device indication could be an occurrence of cardiac arrest, an episode of hemodynamically significant VT, or inducible VT plus syncope at an electrophysiologic (EP) study.

By design, the patients were not taking arrhythmia medication, which is commonly taken by ICD patients to reduce the risk of shocks. All patients in the ablation group underwent mapping (CARTO, Biosense-Webster, Diamond Bar, CA) followed by ablation performed with the patients in sinus rhythm.

SMASH-VT: Clinical end points

End pointAblation group
(n = 64), n (%)
Control group
(n = 64), n (%)
Hazard ratio
(95% CI)
ICD events8 (12)21 (33)0.35 (0.15 - 0.78)
ICD shocks6 (9)20 (31)0.27 (0.11 - 0.67)
ICD storm4 (6)12 (19)0.30 (0.09 - 1.00)
Death6 (9)11 (17)0.59 (0.22 - 1.59)

Patients in the ablation group showed significantly greater rates of two-year survival free of delivered ICD therapy, the primary end point. They also had higher rates of survival free of shocks.

"Ablation of VT is a significant enough procedure that I think only experienced centers should be doing it, initially," Reddy previously told heartwire. He noted the teams performing ablations in the study became better at it as time went on. "As centers get more experience doing VT [substrate] ablation on patients who already have had multiple ICD shocks, they may want to consider doing ablation on this kind of prophylactic basis."

Promise vs practice

As Estes notes in his editorial, the safety and efficacy of catheter ablation depend on the skill of the operator and the selection of patients. "The principal disadvantage of this invasive procedure is the risk of complications," he writes, adding, "It is not clear whether outcomes of catheter ablation would be similar for unselected patients or in less experienced centers."

Estes also writes that while the reduction in ICD therapies is convincing, the study does not address the more clinically important question of the relative efficacy of therapy with antiarrhythmic drugs, the standard front-line therapy for ICD discharges. In addition, he writes that more than 90% of VT episodes can be terminated with antitachycardia pacing, thus reducing the frequency of shocks, with the appropriate use of beta blockers, statins, and contemporary ICD programming.

"As the field of ventricular tachycardia ablation evolves, it is important that we continue to adhere to the fundamental principle of evidence-based medicine, with relevant clinical and economic data derived from human clinical trials forming the foundation for clinical practice," concludes Estes. "The health and well-being of our patients with ICDs who have a history of myocardial infarction are at stake."

Five of the study authors have disclosed various financial relationships with the National Institutes of Health, Biosense Webster, St. Jude Medical, Boston Scientific, Medtronic, Cameron Health, and InnerPulse. The remaining study authors have disclosed no relevant financial relationships. Dr. Estes has disclosed receiving lecture fees from Medtronic, St. Jude Medical, and Boston Scientific.


  1. Reddy VY, Reynolds MR, Neuzil P, et al. Prophylactic catheter ablation for the prevention of defibrillator therapy. N Engl J Med 2007; 357:2657-2665.
  2. Estes NA. Ablation after ICD implantation—bridging the gap between promise and practice. N Engl J Med 2007; 357:2717-2719.
Multidisciplinary Treatment May Benefit Patients With Chronic Low Back Pain

Laurie Barclay

December 27, 2007 — Multidisciplinary treatment strategies are effective for patients with chronic low back pain (CLBP) in all stages of chronicity and should not only be given to those with lower grades of CLBP, according to the results of a prospective longitudinal clinical study reported in the December 15 issue of Spine.

"The treatment of choice for patients with CLBP seems to be a multidisciplinary therapy incorporating multiple treatment components, such as intensive physical exercises and biopsychosocial and behavioral interventions," write Matthias Buchner, MD, PhD, from the University of Heidelberg in Germany, and colleagues. "This prospective clinical study with a 6 months' duration is, to the authors' knowledge, the first to evaluate separately the prognostic value of the chronicity stage in the therapy outcome of patients with CLBP treated with a multidisciplinary biopsychosocial therapy approach."

In this study, 387 patients with CLBP for at least 3 months associated with sick leave for at least 6 weeks underwent standardized multidisciplinary therapy for 3 weeks. At baseline, patients were placed in 3 groups of chronicity graded using the classification of von Korff and colleagues (group A, grades I and II; group B, grade III; group C, grade IV) and were followed prospectively.

At 6-month follow-up, the 3 groups were compared for back-to-work status, generic health status measured with the 36-Item Short Form Health Survey (SF-36), pain intensity measured with the visual analog scale, functional capacity measured with the Hannover back capacity score, and satisfaction with their therapy.

At baseline, patients in group C had a higher pain level, a longer pain history, and more generalized as well as psychosomatic comorbidities vs patients in groups A and B. From baseline to 6 months, all outcome criteria improved significantly in all 3 treatment groups, and the back-to-work rate in the total patient sample was 67.4%.

At the final follow-up, patients with lower grades of chronicity had significantly better outcomes in functional capacity and pain level, but these were mostly attributed to worse values at baseline. At 6 months, there were no significant differences among groups in back-to-work rate, satisfaction with therapy, and the Mental Component Summary of the SF-36.

"According to the results of this study, patients with chronic low back pain also derive significant benefit from a multidisciplinary treatment strategy in higher stages of chronicity," the study authors write. "Therefore, therapy should not be limited to the patients in lower stages of chronicity."

This study has received no external funding, and the study authors have disclosed no relevant financial relationships.

Spine. 2007;32:3060-3066.

Painkiller blocks unwanted effects of morphine

By David DouglasWed Dec 26, 2:42 PM ET

In a mouse model of breast cancer, the COX-2 inhibitor celecoxib (Celebrex) prevents chronic morphine-induced effects on tumor growth without compromising pain relief, scientists report.

"Our study," chief scientist Dr. Kalpna Gupta, told Reuters Health, "provides a proof of principle" that morphine increases COX-2, tumor development, tumor progression and tumor spread, and reduces survival in mice.

"Co-administration of celecoxib prevents these effects of morphine," Gupta said.

In the British Journal of Cancer, Gupta, of the University of Minnesota, Minneapolis and colleagues report that 2 weeks of morphine treatment in mice with breast cancer led to a more than fourfold increase in levels of COX-2 and prostaglandin E2 (PGE2) -- a chemical known to promote inflammation. Morphine administration also increased tumor weight by about 35 percent.

The team found that the addition of celecoxib to the morphine treatment prevented the stimulation of COX-2 and PGE2 and associated tumor-related effects.

In addition, 70 percent of mice treated with morphine only died by day 14 compared to 20 percent of mice given the combination.

"Importantly," continued Gupta, "the combination of morphine and celecoxib provides better analgesia than either of them alone."

"Therefore," he concluded, "clinical trials are warranted to examine that this strategy can be applied to treat pain in patients with cancer."

SOURCE: British Journal of Cancer, November 2007.

Sunday, December 23, 2007

Patients use internet to challenge doctors

One fifth of patients are challenging their doctors' advice or diagnosis using knowledge gained from the internet, a survey suggests.
The survey, conducted for the Southern Cross Medical Care Society, showed 73 per cent used the internet for health information and one in five take the information with them when they see their GP.
Twenty two per cent used information from the internet to challenge their doctor despite one per cent of respondents saying they trusted the information on the web.
Southern Cross chief executive, Dr Ian McPherson, a former GP, said he had mixed feelings on these statistics.
"On one hand it's concerning that people making their own diagnosis could be getting it very wrong.
"On the other hand it's a positive sign that people are increasingly proactive about their health and are prepared to look for information which helps them have a constructive and more informed discussion with their GP.
"They are more likely to go to the doctor better prepared with questions."
Dr McPherson said there was no harm in challenging a medical opinion, but he cautioned people not to put too much faith in the internet to self-diagnose.
Biggest factor in rising health costs are the doctors themselves

There are myriad factors involved in the rising costs of delivering quality care to the population, but the primary factor is with the health care providers themselves.
One of the reasons costs have continued to rise is that physicians and other health care providers are ordering more tests, prescribing more medications and requesting more consultations with specialists. The consultants will then order more tests, prescribe different medications and often request additional assistance from other consultants.
This vicious cycle is compounded by the fact that many of these tests and prescribed medications lead to complications (surgical complications, adverse effects from medications, etc.) that also contribute to rising costs.
Why do we order so many tests? The simple answers are that we "don't want to miss anything" and "because we can." We don't want to miss anything because it would mean that our patients may unnecessarily suffer from an illness by our inability to quickly diagnose the problem. The vast majority of physicians feel the need to help their patients by doing – and ordering more tests fulfills the physician's needs but is not what is necessarily best for the patient. Because we have this desire to help by doing, we frequently do our patients a disservice.
Physicians are accustomed to performing well and answering correctly, as these are the traits necessary to become a physician in the first place. Many feel that if they surround themselves with more data, they will be able to arrive at the correct diagnosis. The problem inherent with this line of reasoning is that the solution to the problem is often buried in a massive, meaningless mesh of data, making it more difficult to arrive at the appropriate conclusion. We as a profession should strive for better data, not just more of it.
The third, often lamented, reason we "don't want to miss anything" is because of an intense fear of litigation. The medical student is frequently reminded by mentors of the likelihood for lawsuits brought about by a missed diagnosis. As a consequence, the practicing physician has a tendency to practice defensive medicine, ordering as many tests and requesting a multitude of additional consultations in an attempt to stave off potential legal action. It is an unfortunate truth that the phrase "first do no harm" has taken new meaning when finished by " your attorney's case."
The final reason we don't want to miss anything has to do with the way we educate new physicians. Prior to the advent of easily obtainable diagnostic tests, physicians primarily used the now ancient art of history and physical examination, whereas today's generation of newly trained physicians (my generation, incidentally) relies more heavily upon the laboratory result as opposed to listening to what the patient has to say. This shotgun approach to ordering a multitude of diagnostic testing has become reflexive in our training institutions and has changed the way physicians practice medicine.
The second part of the initial response to the question of why we order so many tests is much more troubling – "because we can." We can order all of these tests because there is no cost to the ordering physician; in fact, there is often a financial incentive to do so.
The physician is awarded a higher level of complexity when reimbursed if he or she prescribes medications, orders diagnostic testing or requests a consultation with another physician. Requesting consultations can positively affect the physician's business as well. By sending patients to multiple physicians in various specialties, the physician becomes a part of a referral circle, a kind of network that ultimately leads to more patients walking through the door of each physician involved.
To be fair, there are often times when these consultations are not only appropriate, but are necessary as part of a balanced plan of care.
All of the above mentioned problems lead to unnecessary testing, patient angst and a decreased quality of care. We should take into account the degree of complexity in reducing or discontinuing a medication and reward those physicians with the courage and common sense to do so.
The overwhelming majority of physicians want to do the best thing for their patients, but not all of them have been taught the best way to do that.
As such, we should change the way we educate physicians and decrease the amount of financial exposure to litigation that physicians face.
I don't know the best way to remedy these problems, but as a physician, I have become a part of the problem and I know we can do better.
Dr. Steve Cole is a staff physician at Baylor University Medical Center, and works as an allergist/immunologist at Park Lane Allergy and Asthma Center in Dallas. E-mail him at SteveCo@
Vasopressor Support in Septic Shock

Steven M. Hollenberg
When fluid administration fails to restore an adequate arterial pressure and organ perfusion in patients with septic shock, therapy with vasopressor agents should be initiated. The ultimate goals of such therapy in patients with shock are to restore effective tissue perfusion and to normalize cellular metabolism. Although arterial pressure is the end point of vasopressor therapy, and the restoration of adequate pressure is the criterion of effectiveness, BP does not always equate to blood flow; so, the precise BP goal to target is not necessarily the same in all patients. There has been longstanding debate about whether one catecholamine vasopressor agent is superior to another, but different agents have different effects on pressure and flow. The argument about which catecholamine is best in a given situation is best transformed into a discussion about which agent is best suited to implement the therapeutic strategy chosen. Despite the complex pathophysiology of sepsis, an underlying approach to its hemodynamic support can be formulated that takes both pressure and perfusion into account when choosing therapeutic interventions. The efficacy of hemodynamic therapy in sepsis should be assessed by monitoring a combination of clinical and hemodynamic parameters. How to optimize regional blood and microcirculatory blood flow remains uncertain. Thus, specific end points for therapy are debatable and are likely to evolve. Nonetheless, the idea that clinicians should define specific goals and end points, titrate therapies to those end points, and evaluate the results of their interventions on an ongoing basis remains a fundamental principle.
Web 3.0 and medicine Make way for the semantic web

Dean Giustini, UBC biomedical branch librarian
This time last Christmas, medical blogs and RSS feeds were the hot technology topics, and we were debating the merits of newer models of scholarly publishing in web 2.0, such as open access and medical wikis.1 Can web 3.0 be here already?
Recently, a neurologist devised an apt medical metaphor for web 3.0. He suggested that, "The development of the graphical web from its early days in 1995 to the social web of late 2007 is comparable to the developing brain." He went on to say that, "Whereas web 1.0 and 2.0 were embryonic, formative technologies, web 3.0 promises to be a more mature web where better ‘pathways’ for information retrieval will be created, and a greater capacity for cognitive processing of information will be built." (Personal communication, A Wong, 2007.)
So what is web 3.0, and why is it called the semanticweb (table)? Although both terms are used interchangeably, they convey slightly different, if complementary, views of the new web. The web 3.0 label is often used as a marketing ploy for "the next big thing." An important feature of web 3.0 is that it enables computers to talk to each other so that they can perform the tasks necessary for us to do our work. However, a primary feature of web 3.0 is that it uses metadata—data about data. This will transform the web into a giant database, and organise it along the lines of PubMed, or one of our trusted medical library catalogues.2
Somehow, the term semantic web has escaped the reproach of web 3.0, perhaps because it was coined by the respected web expert Sir Tim Berners-Lee in his landmark paper in Scientific American.3 His ideas continue to have tremendous salience. Berners-Lee’s view is that we need to use semantic annotation to express the meaning latent in web documents, by drawing out inferences in documents deep within the web. As a pioneer in search technology, and director of the World Wide Web Consortium, Berners-Lee maintains that access to a global "web of data"—what weaves the entire web together into a coherent whole—should help to solve humankind’s most complex problems.4
To understand why we need web 3.0, let’s examine the current state of the web. Currently, access to endless reams of unorganised information in web 2.0 shifts the online habits of doctors to searching, not finding. Consequently, medical librarians believe that it is necessary to build better mechanisms for information retrieval.5 6 As a colleague said to me recently, "we need findengines, not search engines."
In medicine, finding the best evidence has become increasingly difficult, even for librarians. Despite its constant accessibility, Google’s search results are emblematic of an approaching crisis with information overload, and this is duplicated by Yahoo and other search engines. Consequently, medical librarians are leading doctors back to trusted sources, such as PubMed, Clinical Evidence, and the Cochrane Library, and even taking them to their library bookshelves instead. Unless better channels of information are created in web 3.0, we can expect the information glut to continue.
Web 3.0 is likely to have a big effect on medicine in 2008. In bioinformatics, it will become more common to process ever larger amounts of data. In fact, experts in bioinformatics already search for data from disparate systems, and they have started to build rich semantic relations into information tools for knowledge discovery. Finally, greater capacity for creating knowledge in medicine will be possible if we have the will to publish clinical data openly and transparently, and subject it to scrutiny.7
Developing a more personalised healthcare system will be an important challenge for doctors in web 3.0. In an era of greater personalisation, treating patients’ health problems according to their genetic profiles will depend on using the latest information technologies.8 Even the treatment of new diseases and warning systems for natural disasters will benefit from the merging of epidemiological datasets with virtual, three dimensional tools like Google Earth. Making the search for health information efficient and responsive to patients’ needs will also help reduce the costs of medical treatment.
Social software enthusiasts may well find that the new web will be fertile ground for the creation of knowledge. Although already popular, wikis may well serve as platforms for the exploration of web 3.0. One innovative wiki—Wikiproteins—is already using semantic technologies. In contrast to other wikis, Wikiproteins imports data mined from several of the world’s leading biomedical databases, such as PubMed, UniProt, and the National Library of Medicine. Its integrated entries are a useful combination of genetic information and scientific literature. Notably, the confluence of databases in Wikiproteins yields more than two million factual associations for data mining and over five billion associated pairs.9
Each new version of the web should be a better iteration of its predecessor, and web 3.0 should be no exception. In medicine, we should focus on the ability to locate trusted clinical information, while creating the means to produce new knowledge. Information retrieval in web 3.0 should be based less on keywords than on intelligent ontological frameworks, such as the National Library of Medicine’s Unified Medical Language System, Medline’s trusted MeSH vocabulary, or some other tool. The National Library of Medicine is working on automated indexing, which may be part of the solution for searching the biomedical web.10 Finally, as we move further into the digital age, our trusted print libraries must continue to be well funded and should not be forgotten in the midst of the intelligent web.
The question of whether and—two popular social tagging sites—will be useful in web 3.0 remains doubtful.11 Social tagging or "indexing" has limitations because of poor control of synonyms, homonyms, spelling conventions, and other linguistic variations. Think about the myriad ways we describe a heart attack; these variations have enormous implications for searching and require control to optimise retrieval. A smarter medical web is coming. Its two most exciting features will be the better organisation of documents and a deeper use of the knowledge base in medicine. In terms of searching, the semantic web should resemble a library catalogue, where documents are described and given meaningful access points for easy retrieval. However, in getting to web 3.0, let’s aim for something better than the current web, not the incoherent mess of web 2.0. Logically, web 3.0 should bring order to the 21st century web in the same way that Dr John Shaw Billings’s Index Medicus brought order to medical research back in the 19th century.12 As a medical librarian, I sincerely hope that web 3.0 will return us to some of the time honoured principles of my profession.
Data mining—a process of knowledge discovery or retrieval of hidden information from data banks and clusters of databases
Mashup—a web application or site that mixes content from multiple sources
RSS (really simple syndication)—a format for sharing content between different websites
Semantic web—a project that intends to create a universal medium for information exchange from 2008 and beyond by putting documents with computer processable meaning (semantics) on the world wide web
Semantics—a term derived from the Greek to give signs, meaning, or to make significant. Semantics refers to aspects of meaning as expressed in language or other systems of signs
Social tagging—the application of freely chosen labels, or tags, to web documents, web pages, and photo sharing sites, such as
Web 3.0—a term used to describe the evolution of the web, and our responses to it, in finding and organising new information
Wiki—a website or similar online resource that allows users to add and edit medical information collectively
Dean Giustini, UBC biomedical branch librarian
1 University of British Columbia Biomedical Branch Library, Diamond Healthcare Centre and Vancouver Hospital, BC, Canada V5Z 1M9

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False-Positives in the PCI Era: Roughly 1 in 10 Patients Sent to Cath Lab Unnecessarily

Shelley Wood
December 21, 2007 — Having emergency-room physicians diagnose ST-segment-elevation MI (STEMI) and "activate" cardiac cath labs directly — cutting out the delay associated with seeing a cardiologist — is a key recommendation for efforts to trim door-to-balloon times for patients with STEMI. But a new analysis suggests that this strategy may lead to false-positive activation of cath labs anywhere from 9% to 14% of the time.
Writing in the December 19, 2007 issue of the Journal of the American Medical Association, Dr David M Larson (Ridgeview Medical Center, Waconia, MN) and colleagues point out that hospitals planning and budgeting for strategies to cut door-to-balloon times will need to take into account this relatively common and unavoidable consequence of direct cath-lab activation [1].
To heartwire, Larson, an emergency room (ER) physician, commented that he thinks a false-positive rate somewhere in the region of what they found is appropriate. In the thrombolytic era, he notes, the false-positive rate of patients who received lytics and later were found not to have a myocardial infarction (MI; by cardiac biomarkers) was about 10%; false-positive rates in the percutaneous coronary intervention (PCI) era have not previously been reported, with or without door-to-balloon time-saving strategies. Larson also thinks that while hospitals should always strive to reduce the rates of patients being sent to the cath lab unnecessarily, there needs to be a balance.
"There are a lot of cases that are in the gray zone," he said. "If you're more specific, and you decrease the rate of false positives, you're probably going to increase your rate of false negatives. It's a trade-off."
Larson et al reviewed all cases of suspected STEMI patients presenting to the Minneapolis Heart Institute or transferred from one of 30 community hospitals — a total of 1345 patients between March 2003 and November 2006. In all cases, emergency-department staff, on the basis of electrocardiogram (ECG) results, activated the cath lab at the tertiary hospital before transferring patients for angiography. In the authors' subsequent review, however, 14% of patients were found to have no culprit coronary artery and 9.5% had no significant coronary artery disease. Of those with no coronary artery disease (CAD), 38% had positive cardiac biomarkers, pointing to myocarditis (31%), stress cardiomyopathy (31%), or STEMI confirmed by cardiac magnetic resonance imaging (MRI) — in some of these patients, angiography did not pave the way for PCI but was at least an appropriate diagnostic test. In all, just 9.2% of patients had both negative cardiac biomarkers and no culprit artery, which the authors say believe is likely the "true measure" of unnecessary cath-lab activation in this study.
Sometimes you do need to slow down
In an accompanying editorial, Dr Frederick A Masoudi (Denver Health Medical Center, CO) points out that the push in recent years to reduce door-to-balloon times may have the unintended consequence of increasing false-positive rates [2]. "In the case of primary PCI, the view of quality should extend beyond the time to treatment to include patient selection and ultimately to outcomes," he writes. To reduce the number of false positives that arise from overly zealous efforts to shorten door-to-balloon times, false-positive rates could, like door-to-balloon times, be a measure in the overall assessment of hospital performance.
Larson agrees: "There's so much emphasis on door-to-balloon time and time to reperfusion; I think sometimes we have to realize that there are cases where we need to slow down and maybe get another ECG or an echocardiogram and not penalize people for slower door-to-balloon times in those cases. When you're looking at quality, it's not just the process measures like time to treatment, it's patient selection as well. If one hospital has a false-positive rate of 25% and the standard in the community is 10%, you have to take a closer look at that."
But Larson also believes there is "always room for improvement." In his study, roughly 2% of electrocardiograms were "overread," resulting in patients heading to the cath lab unnecessarily. Better education would help reduce this problem, and centers with higher rates of false positives could perhaps be targeted for this kind of education, Larson suggests. He also notes that many patients who undergo an urgent diagnostic catheterization and are not found to have occlusive disease are patients who would likely have ended up undergoing angiography at a later date anyhow and, in some cases, may at least be less at risk from an invasive catheterization than if they underwent unnecessary fibrinolytic therapy: for example, patients having a dissection or who have pericarditis.
Larson also emphasized that the results should not be interpreted to mean that a cardiologist should see each and every patient with presumed STEMI in the emergency room—bypassing the cardiologist has proved key to improving door-to-balloon times. "There should always be the opportunity, on questionable cases, to get more data, get help from a cardiologist if necessary, have someone else look at the ECG, without penalizing somebody for having a slower door-to-balloon time. But I don't think we should change the whole system: most of the cases — 90% — are clear-cut. You don't want to hurt the whole system because of the remaining 10% of patients."
Know your rates
Also commenting on the study for heartwire, senior author and cardiologist Dr Timothy Henry (Abbott Northwestern Hospital, Minneapolis, MN) noted that this study "sets a benchmark."
"Everyone talks about false positives, but no one knows what their rates are or what the rates should be," he said. "If your false-positive rate is 2% or 5%, you're doing something wrong and you're missing patients. But if your false-positive rate is 25%, you need to be talking to people about what you could do differently. . . . The most important thing is that everyone should know what their own rate is. We've been so focused on reducing door-to-balloon times that we've forgotten about some of these other things."
Larson, DM, Menssen KM, Sharkey SW, et al. "False-positive" cardiac catheterization laboratory activation among patients with suspected ST-segment elevation myocardial infarction. JAMA. 2007;298:2754-2760.
Masoudi FA. Measuring the quality of primary PCI for ST-segment elevation myocardial infarction. Time for balance. JAMA. 2007;298:2790-2791.
New Deaths Spur Renewed FDA Fentanyl Patch Warning

By Peggy Peck
ROCKVILLE, Md., Dec. 21 -- Two years after the FDA warned that fentanyl transdermal devices were linked to 120 deaths, patients are still dying because physicians still misprescribe the patches and patients still misuse them, the agency warned today.
But the FDA said it couldn't give an exact death total, citing the vacation absence of staffers in the know. Rob Rappaport, M.D., director of the FDA's Division of Anesthesia, Analgesia, and Rheumatology Products, expected hard numbers in a week or so.
But he stressed at a news conference that the absolute number was "not that large and the important issue is not how large a number, but rather that the product is still not being used correctly."
Fentanyl patches, he said, should only be used in patients who are opioid tolerant. Using it in patients who have not yet developed opioid tolerance was likely to cause serious respiratory depression.
Moreover, the patches should only be used in patients with severe, chronic pain. The patch should not, he said, be used to treat headache pain, which was the case with at least one adverse event case reported to the FDA.
"The reports indicate that doctors have inappropriately prescribed the fentanyl patch to patients for acute pain following surgery, for headaches, occasional or mild pain, and other indications for which a fentanyl patch should not be prescribed," the FDA said.
"In addition, the reports indicate that patients are continuing to incorrectly use the fentanyl patch by replacing the patch more frequently than directed in the fentanyl patch instructions, applying more patches than prescribed, or applying a heat source to the patch."
In the two years since the first fentanyl warning, some groups have urged the FDA to limit physicians permitted to prescribe fentanyl -- reserving this, for instance, to pain medicine specialists.
Dr. Rappaport said that approach would unnecessarily limit patients' access to an effective analgesic. He said an estimated 60 million Americans suffer chronic pain syndromes, "but there are only about 4,000 pain medicine specialists."
In addition to this second safety warning, the FDA said it has ordered manufacturers of fentanyl patches to create medication guides for patients that describe in detail the dangers of fentanyl overdoses and simple directions about proper use.
The guides will, for example, warn patients not to expose the patch to heat with heating pads, heated waterbeds, or hot tubs. Heat exposure, Dr. Rappaport said, speeds release of fentanyl into the bloodstream.
Patients who have high fever (higher than 102) should also get in touch with a physician immediately, he said.
He said patients would also receive detailed information about how often fentanyl patches should be replaced -- including replacement of patches that fall off accidentally.
Depression Depresses HIV Treatment Response

By Michael Smith
OAKLAND, Calif., Dec. 21 -- More than four in every 10 HIV patients are clinically depressed, a condition that affects how well they respond to anti-HIV drugs, researchers here found.
The good news, however, is that treatment with selective serotonin reuptake inhibitors (SSRIs) appears to restore the benefit of highly active antiretroviral therapy (HAART), according to Michael Horberg, M.D., director of HIV/AIDS for Kaiser Permanente.
In a retrospective analysis of a cohort of 3,359 HIV patients, 42% also had a diagnosis of depression and 36% of those were using SSRIs, Dr. Horberg and colleagues reported online in the Journal of Acquired Immune Deficiency Syndromes.
"The take-home point here is that there is a very high prevalence of depression among HIV patients," Dr. Horberg said.
"All HIV patients should be screened for depression," he said, and if it's found, "treatment for depression -- not just with SSRIs -- should be considered concomitantly, because one helps the other."
The researchers analyzed health records of HIV patients in eight states, enrolled in the Kaiser Permanente and Group Health Cooperative HMOs, who began a new HAART regimen from January 2000 through December 2003.
Of the 3,359 patients who met the criteria, 1,961 had not been diagnosed with depression and served as a control group.
The researchers found:
Depression was associated with significantly decreased odds of achieving 90% or better adherence to HAART. The odds ratio was 0.81, with a 95% confidence interval from 0.70 to 0.98, which was significant at P=0.03.
The condition was also associated with significantly lower odds of a serum HIV RNA level of less than 500 copies per milliliter. The odds ratio was 0.77, with a 95% confidence interval from 0.62 to 0.95, which was significant at P=0.02.
The impact of depression on viral load might just be a function of poorer adherence to HAART, but interestingly, Dr. Horberg and colleagues found, the negative association persisted even when depressed patients were taking their HAART medication properly.
In a multivariable analysis taking HAART adherence into account, depressed patients were 12% less likely to get below the 500-copy level, a difference that remained significant at P=0.05, the researchers reported.
The finding implies that depression itself has an impact on the effect of HAART, over and above any possible impact on adherence, Dr. Horberg said.
Dr. Horberg said he and colleagues were puzzled by one finding, that there appeared to be little benefit of SSRIs among depressed patients who had been on HAART and were switched to a new regimen -- with the addition of an SSRI -- during the study period.
There might simply have been too few patients (428) to see an effect, Dr. Horberg said. But equally, those patients might have been severely depressed or perhaps using an SSRI that was not effective for them.
"We couldn't look at the degree of severity," he said.
The study was limited by its retrospective design, but Dr. Horberg said he and colleagues are planning a prospective study to confirm the findings.
The study was supported by the Garfield Memorial Research Fund of Kaiser Permanente. Dr. Horberg is an employee of the company.
Primary source: Journal of Acquired Immune Deficiency SyndromesSource reference:Horberg MA, et al "Effects of depression and selective serotonin reuptake inhibitor use on adherence to highly active antiretroviral therapy and on clinical outcomes in HIV-infected patients" J Acquir Immune Defic Syndr 2007.
Physical Activity Linked to Lower Risk of Vascular Dementia But Not AD

Susan Jeffrey
December 21, 2007 — Results of a new prospective study have found an association between increasing levels of physical activity and a lower risk for vascular dementia, but not for Alzheimer's disease (AD). "Our findings show moderate physical activity such as walking and all physical activities combined lowered the risk of vascular dementia in the elderly, independent of several sociodemographic, genetic, and medical factors," first author Giovanni Ravaglia, MD, from University Hospital S. Orsola-Malpighi, in Bologna, Italy, said in a statement from the American Academy of Neurology. "It's important to note that an easy-to-perform moderate activity like walking provided the same cognitive benefits as other more demanding activities."
Unlike some previous reports, they did not find a relationship between increased activity and reduced Alzheimer's disease risk. However, the researchers note they cannot rule out that they may have missed such an association because of a lack of statistical power.
Their findings are published online December 19 in Neurology.
Walking Away from Dementia?
Observational and intervention studies have consistently shown an association between physical exercise and better cognitive performance in selected samples of older adults, although not all studies have confirmed this finding, the authors write.
Longitudinal studies of this link in the elderly are fewer and have had inconsistent results, they note. "A lower risk of all-cause dementia and AD among subjects regularly practicing low- to medium-intensity physical activities was found in some population-based studies but not in others," they write. "Moreover, only a few investigations examined the effect of physical activity on vascular dementia (VaD) risk, and none reported an association."
To look at the effect of physical activity on the risk for AD and VaD, Dr. Ravaglia and colleagues used data from the Conselice Study of Brain Aging (CSBA), a prospective, population-based cohort of 749 Italian subjects aged 65 years and older who were cognitively normal in 1999–2000 after an extensive assessment for clinically overt and preclinical dementia. Baseline physical activity was measured as energy expenditure on activities of different intensities, including walking, stair climbing, moderate activities, vigorous activities, and total physical activity.
During 2003–2004, subjects underwent a follow-up examination looking for overt dementia. Over nearly 4 years of follow-up, there were 86 incident cases of dementia, including 54 cases of AD and 27 of VaD.
The researchers found that, after adjustment for sociodemographic and genetic confounders, the risk for VaD was significantly lower for the upper vs lower tertiles for walking, moderate activity, and total physical activity, associations that persisted after vascular risk factors and overall health status were accounted for.
After similar adjustment for sociodemographic and genetic confounders, the risk for AD was not associated with measures of physical activity, they write. These results did not change after further adjustment for vascular risk factors and overall health and functional status.
"However, because of the width of the CIs for AD found in the CSBA study, it cannot be excluded that significant results for this dementia subtype may have been missed by lack of statistical power," Dr. Ravaglia and colleagues write. "Therefore, we caution the reader against concluding that this study provides definite evidence that AD is not preventable through exercise."
More research on the biologic mechanisms linking physical activity and cognition is needed, they note, but they float a variety of "not mutually exclusive" hypotheses on how cognition may benefit from physical activity. For example, physical activity may improve cerebral blood flow and lower the risk for cerebrovascular disease. Alternatively, activity may stimulate synaptic plasticity, secretion of trophic factors, neurotransmitter synthesis, and neurogenesis to increase cognitive reserve or decrease the secretion of stress hormones such as cortisol that may be toxic.
"Finally, more than from exercise itself, the beneficial effects of physical activity on cognition might result, all or in part, from the mental and social stimulation related to an active lifestyle."
The study was supported by grants from the Italian Ministry of University and Scientific Research (basic-oriented research funds). The authors report no conflicts of interest.
Neurology. Published online December 19, 2007.
Allergies may protect against pancreatic cancer

By Michelle Rizzo
Having a history of allergies or hay fever may offer protection from deadly pancreatic cancer, according to a study appearing in the International Journal of Cancer.
Ayelet Eppel, of Mt. Sinai Hospital, Toronto, Ontario, Canada, and colleagues examined the association between a history of allergies or asthma and the risk of pancreas cancer in a population-based, case-control study in Ontario.
They identified cases of pancreatic cancer through the Ontario Cancer Registry and recruited control subjects from the Ontario Familial Colorectal Cancer Registry.
A total of 276 pancreatic cancer cases and 378 controls were included in the study.
The investigators found that a history of allergies or hay fever was associated with a significant 57 percent reduction in the risk of pancreatic cancer.
The reduction in risk was stronger in men than in women. There was no association between history of asthma and the risk of cancer of the pancreas.
"Further research is needed to replicate these findings," Eppel told Reuters Health.
"If replicated, our findings may be of importance to understanding the biological mechanisms involved in pancreas cancer development -- for example, the role of the immune system," the researcher explained, adding: "The association between allergies and certain cancers has been found in other studies."
SOURCE: International Journal of Cancer, December 2007.
Weight Loss Surgery May Help Less Severely Obese

FRIDAY, Dec. 21 (HealthDay News) --The morbidly obese may not be the only people who should be eligible for bariatric surgery to lose weight, U.S. researchers report.
People with a body-mass index (BMI) less than the required 40 could still reap heart health benefits from the surgery, they say.
BMI is calculated based on height and weight. A healthy BMI ranges between 18.5 and 25. A person with a BMI of 40 -- for example, someone 5 feet 9 inches tall and 270 pounds -- is considered morbidly obese. According to the Centers for Disease Control and Prevention, one in three adults is obese.
Bariatric surgery options include gastric bypass and lap band surgeries. Typically, a person must have a BMI of 40, or be at least 100 pounds over their healthy weight, to qualify for these surgeries. People who have a BMI greater than 35 and suffer from a life-threatening illness, such as non-insulin dependent diabetes, sleep apnea or heart disease, can also qualify.
However, researchers at University of Texas Southwestern Medical Center at Dallas published data in the December issue of Surgery for Obesity and Related Diseases suggesting that some otherwise healthy overweight people with a BMI lower than 40 may benefit. And they may benefit more from the surgery than people who are morbidly obese, the team added.
The study is among the first to evaluate the risk-factor relationship between BMI and cardiovascular disease as it relates to bariatric surgery criteria, said study author Dr. Edward Livingston, chairman of GI/endocrine surgery at UT Southwestern.
"Our results show that cardiovascular risk factors do not necessarily worsen with increasing obesity," Livingston said in a prepared statement. "They also support the concept that obesity, by itself, doesn't trigger an adverse cardiovascular risk profile or increased risk of death."
The research team analyzed health data from more than 17,200 adults who had a BMI greater than 20 and had participated in the Third National Health and Nutrition Examination. The researchers assessed their heart disease risk factors with respect to their BMI. They found a subgroup of people whose BMIs were lower than 40 but who had significant heart disease risk factors.
This suggests that some patients who are obese but not morbidly obese could benefit from bariatric surgery, which can help reduce cardiovascular disease, said Livingston.
The research team theorized that some morbidly obese people may be more efficient than moderately overweight people at storing fat in their cells, so it does not have as great an effect on the cardiovascular system.
More information
To learn more about body-mass index and calculate your own, visit the U.S. Centers for Disease Control and Prevention.

Friday, December 21, 2007

Updated Food Pyramid for Older Adults Offers Graphic

By Judith Groch
BOSTON, Dec. 20 -- Patients 70 and older seeking sound nutritional advice have been given their own food pyramid, complete with suggestions for ways to reduce extra trips to the grocery store.The goal of the food pyramid for older patients is to make the information accessible on paper for those who may not be adept in computers and Web sites, where the standard USDA MyPyramid resides. The older-adult version also has small but important differences that distinguish it from the standard pyramid.For instance, the new "Modified MyPyramid for Older Adults" emphasizes packaged, canned, or frozen fruits and vegetables in addition to the fresh variety, Alice H. Lichtenstein, D.Sc., of Tufts University here, and colleagues reported online in the Journal of Nutrition. The new graphic will be published in the January issue.
Bags of frozen pre-cut vegetables that can be resealed or single-serve portions of canned fruit may be easier to prepare and have a longer shelf life, while dried fruits are an excellent source of fiber, the Tufts team wrote.
Such factors, the researchers added, are important when age or weather make shopping less likely. For a number of reasons, these forms may be better suited to older adults.
Patients older than 70 have unique dietary needs, Dr. Lichtenstein said. They may need fewer calories because they are less physically active and their metabolic rates slow, yet their bodies still require the same or higher levels of nutrients.
Furthermore, she said, they may need additional guidance about the forms of food that can best meet their needs and about the importance of sufficient fluid intake and physical activity.
The Tufts version of the pyramid in graphic form is not intended to substitute for the standard MyPyramid, which is now an Internet-based program allowing for the calculation of individualized food-based dietary choices and providing supplemental information.
However, the Tufts researchers wrote that they were concerned about issues related to computer availability, Web access, and Internet literacy among older adults, suggesting that a graphic version of MyPyramid was needed.
Thus, the Modified MyPyramid for Older Adults appears in a colorful illustrated format consistent with the familiar standard MyPyramid drawing.
The Modified MyPyramid stresses nutrient- and fiber-rich foods and food sources for nutrients rather than supplements. Fluids and physical activity icons appear at the foundation of the Pyramid.
A flag to maintain awareness of a possible need for supplemental forms of calcium, and vitamins D and B-12 waves from the top of the pyramid.
The major features in the Modified Pyramid graphic that differ from the standard food guide pyramid are the expanded presentations of food icons throughout the pyramid highlighting good choices within each category. A row of water glasses and little drawings of physical activities, such as walking, and house and yard work, run along the base of the illustration.
The flag at the top of the pyramid suggests that some older adults, due to biological changes, may need supplemental vitamins B-12 and D, and calcium, if the person's health care provider agrees. However, the researchers emphasized that the majority, if not all, of the nutrients should come from food and not supplements.
The graphic icons in the pyramid emphasize physical activity and fluid intake (including soup), plus foods in the following categories:
Whole, enriched, and fortified grains and cereal, such as brown rice and 100% whole wheat bread
Bright colored vegetables, such as carrots and broccoli
Deep-colored fruit, such as berries and melon
Low- and non-fat dairy products, such as yogurt and low-lactose milk
Dry beans and nuts, fish, poultry, lean meat, and eggs
Liquid vegetable oils and soft spreads low in saturated and trans fat.
"We do not intend the graphic to accomplish all the functions that the interactive computer program does or substitute for it. The intent is to incorporate icons within the graphic that serve to raise awareness of the unique needs of older adults and how to meet them," the researchers said.
The researchers reported no conflicts of interest.
This study was supported by a grant from the Ross Initiative on Aging at Tufts University and the USDA.
Primary source: Journal of NutritionSource reference:Lichtenstein A, et al "Modified MyPyramid for older adults" J Nutr 2008; 138: 5-11.
No Easy Choice for Fracture Prevention Agents

By Crystal Phend
SANTA MONICA, Calif., Dec. 20 -- Choosing among the multitude of agents to prevent osteoporotic fractures is no snap, according to a systematic review.The review showed a disjointed field with few and poor comparisons among therapies, Margaret Maglione, M.P.P., of the Rand Corporation here, and colleagues reported online in the Annals of Internal Medicine.These findings followed on the heels of a report this week in the Journal of the American Medical Association reinforcing the need for preventive therapy for older women with evidence of a vertebral fracture regardless of bone-mineral density. In the systematic review, no studies have shown one treatment for osteoporosis superior to another, and no head-to-head study has been powered to detect even large differences between therapies.
"Data are insufficient to determine the relative efficacy or safety of these agents," reported Maglione and colleagues.
"It is unlikely that such studies will be performed unless they are required as part of the approval process for these agents," they added.
Their systematic review included 76 randomized trials and 24 meta-analyses evaluating bisphosphonates, calcitonin, estrogen, teriparatide (Forteo), selective estrogen receptor modulators, testosterone, and vitamin D and calcium.
For adverse events, the review included 417 randomized trials, 25 other controlled clinical trials, 11 open-label trials, 31 large observational studies, and nine reports of osteonecrosis among bisphosphonate users.
There was good evidence -- a total sample size greater than 1,000 and consistent findings across studies -- that alendronate (Fosamax), etidronate (Didronel, not FDA approved for osteoporosis treatment), ibandronate (Boniva), risedronate (Actonel), calcitonin, parathyroid hormone (PTH 1-34), and raloxifene (Evista) prevented vertebral fractures compared with placebo.
Likewise, good evidence from multiple trials and meta-analyses suggested alendronate and risedronate prevented nonvertebral and hip fractures compared with placebo.
Although zoledronic acid (Zometa) is not FDA approved for treatment or prevention of osteoporosis, the evidence was good for efficacy against vertebral and nonvertebral fractures in high-risk populations and was fair for hip fracture risk reduction.
A large randomized trial reported that PTH 1-34 prevented nonvertebral fractures, but the evidence was inconsistent with no benefit seen in two smaller trials.
Estrogen was supported by good evidence for reduction of vertebral, nonvertebral, and hip fractures compared with placebo. The largest meta-analysis looking at estrogen showed a 55% reduction in fracture compared with placebo (relative risk: 0.45, 95% confidence interval: 0.45 to 0.98). However, a second large meta-analysis found that the reduction was not significant (RR: 0.68, 95% CI: 0.41 to 1.07).
The review turned up no evidence that tamoxifen (Nolvadex) or testosterone reduce fracture risk, and neither is FDA approved for treatment or prevention of osteoporosis.
Calcium by itself was not effective compared with placebo in a meta-analysis or several large randomized trials for vertebral, nonvertebral, and hip fractures in postmenopausal women.
But, a large study showed that adherence might obscure calcium's benefit. One trial showed a significant risk reduction in nonvertebral fractures among participants who consumed at least 80% of their calcium tablets (RR: 0.63, 95% CI: 0.41 to 0.96).
Vitamin D did not reduce risk of vertebral, nonvertebral, and hip fractures compared with placebo in meta-analyses or a large trial with the exception of one meta-analysis that found a significant 23% reduced risk of nonvertebral fractures and 26% reduction in hip fractures for vitamin D2 or D3.
Evidence was better for the vitamin D analogues. Vertebral fracture risk dropped significantly with 1, 25-hydroxyvitamin D and 1-hydroxyvitamin D compared with placebo (RR range: 0.52 to 0.64 across three meta-analyses). Nonvertebral and hip fracture risk was reduced significantly by vitamin D analogues in four of seven reported comparisons (RR range: 0.16, 95% CI: 0.04 to 0.69, to 0.87, 95% CI: 0.29 to 2.59).
While vitamin D may not universally reduce risk, the data did "suggest that vitamin D analogues reduce the risk for vertebral fractures," they said, "and that, in high enough doses, standard vitamin D may prevent fractures in some high-risk populations."
No randomized trials comparing bisphosphonates showed superiority for any agent in fracture prevention. The one head-to-head comparison looking at fracture risk showed no difference between risedronate and etidronate against vertebral fractures (RR: 0.66, 95% CI: 0.32 to 1.36).
The sixteen trials comparing agents across classes were "too small and too short to detect clinically important differences in fracture incidence between groups," the researchers said.
The only other head-to-head comparison of fracture outcomes, between raloxifene and alendronate, was underpowered and revealed no difference in the hip, wrist, or total vertebral fractures, although there were fewer moderate-to-severe vertebral fractures with raloxifene (P=0.04).
Maglione and colleagues concluded that bisphosphonates have not been shown better for prevention of fractures than calcitonin, calcium, or raloxifene, or estrogen.
The agents were associated with adverse events, including thromboembolic events with raloxifene and estrogen and esophageal symptoms with bisphosphonates. Despite several reports of osteonecrosis of the jaw with high-dose, intravenous bisphosphonates, the investigators could not calculate the risk overall.
Furthermore, there was limited evidence for lower risk populations, including men and women with osteopenia.
The review was conducted under contract with the Agency for Healthcare Research and Quality. One of the researchers reported stock ownership or options in Johnson & Johnson and another reported being employed by WellPoint.
Primary source: Annals of Internal MedicineSource reference:MacLean C, et al "Systematic review: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis" Ann Intern Med 2008; 148.
Bevacizumab-Interferon Duo Improves Progression-Free Survival in Kidney Cancer

By Charles Bankhead
VILLEJUIF, France, Dec. 20 -- When bevacizumab (Avastin) is added to interferon, the combo significantly improves progression-free survival in advanced renal cell carcinoma, investigators here reported.
The combination therapy doubled the duration of progression-free survival compared with interferon alone, Bernard Escudier, M.D., of Gustave Roussy Institute, and colleagues reported in the Dec. 22 issue of The Lancet. The frequency, severity, and mortality of adverse events did not differ between patients treated with interferon alone or interferon plus bevacizumab.
"The data presented here raise intriguing questions regarding the future of therapy for metastatic renal cell carcinoma," the authors said. "The availability of a variety of active agents provides increased treatment options and the opportunity to provide several lines of therapy and improved survival."
Metastatic renal cell carcinoma is resistant to conventional therapy. Until recently, standard systemic therapy consisted of interleukin-2 or interferon, both of which produced modest response rates at a price of substantial toxicity.
More recently, the tyrosine kinase inhibitors sorafenib and sunitinib have been approved for treatment of metastatic renal cell carcinoma. Both have been shown to improve progression-free survival in patients whose disease did not respond to interferon or IL-2, the authors noted. However, only the mammalian target of rapamycin inhibitor temsirolimus has improved overall survival compared with interferon alone.
In preliminary studies in advanced renal cell carcinoma, bevacizumab, a humanized monoclonal antibody that inhibits vascular endothelial growth factor, improved progression-free survival and time to progression, and induced durable responses lasting three to five years in some patients.
Dr. Escudier and colleagues reported findings from a randomized, double-blind phase III trial involving 649 patients with untreated metastatic disease. The patients were randomized to interferon alfa-2a (9 MIU subcutaneous three times a week) plus bevacizumab (10 mg/kg every two weeks) or interferon alfa-2a and placebo.
The primary endpoint was overall survival, and secondary endpoints included progression-free survival and safety. At a planned interim analysis, investigators changed the primary endpoint to progression-free survival, acknowledging that new second-line therapies that had become available during the trial could confound the results.
At the time of unblinding. 230 of 325 patients on combination therapy had progressed, as had 275 of 316 in the interferon-placebo group. Additionally, 114 deaths had occurred in the bevacizumab arm and 137 in the placebo arm.
Median duration of progression-free survival was 10.2 months with bevacizumab versus 5.4 months with placebo (P=0.0001).
"Increases in progression-free survival were seen with bevacizumab plus interferon alfa irrespective of risk group or whether reduced-dose interferon alfa was received," the authors reported.
The most common grade 3+ adverse events were fatigue (12% with bevacizumab versus 25% with placebo) and asthenia (10% with bevacizumab and 7% with placebo). Adverse event-related mortality was 2% in each treatment arm.
In a commentary that accompanied the article, Robert J. Motzer, M.D., and Ethan Basch, M.D., of Memorial Sloan-Kettering Cancer Center in New York, noted that response to therapy was assessed by individual investigators. "Lack of independent review of response might have affected the proportion of patients with reported responses, and therefore affected perceived progression-free survival outcomes."
Dr. Escudier disclosed consulting fees and honoraria from Roche, Bayer, Wyeth, Pfizer, Inate, and Antigenics. Dr. Motzer disclosed honoraria from Bayer/Onyx, current research funding from Genentech, Wyeth Research, Pfizer, and Novartis, and past research funding from Roche and Schering-Plough.
Primary source: The LancetSource reference:Escudier B, et al "Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomized, double-blind phase III trial" Lancet 2007; 370: 2103-2111. Additional source: The LancetSource reference: Motzer R, Basch E, "Targeted drugs for metastatic renal cell carcinoma" Lancet 2007; 370: 2071-2073.
CV Risk Factors Associated With VTE

Lisa Nainggolan
December 20, 2007 (Greenville, TX)– The latest statistics compiled by the American Heart Association (AHA) show that deaths from cardiovascular disease in the US continue to decline, but there has been no drop in nonfatal cardiovascular events, which often turn out to be extremely disabling. In addition, risk factors such as obesity and diabetes are most definitely on the rise, and this will have major clinical implications, say Dr Wayne Rosamond (University of North Carolina, Chapel Hill) and colleagues in a report published online December 17, 2007 in Circulation [1].
A coauthor of the year-end report, Dr Donald Lloyd-Jones (Northwestern University, Chicago, IL), told heartwire: "It's nice to see those mortality data coming down, but that's not the whole story by any stretch. There are some very concerning trends, both in nonfatal events and the disability that results from them and in risk-factor levels that are pretty clear indicators that we are not going to be celebrating long, and in fact we should not be celebrating at all."
Physicians, among others, he says, are going to have to address these issues. "What we are seeing here is the tip of the iceberg. There are real reasons to be concerned. We need to do a much better job at a public-health level of educating the public about their real risks from cardiovascular disease. And we doctors need to do a much better job of having patients know their numbers in terms of their risk factors and having concrete plans for addressing those risk factors for everyone."
CHD single leading cause of death
The 123-page report shows that in 2004--the most recent year for which statistics are available--the age-adjusted CVD death rate per 100 000 persons in the US was 288.0, compared with 307.7 in 2003.
CVD is the number-one cause of death, listed as the underlying cause in 869 724 deaths, compared with 911 163 deaths in 2003. Cancer was the second leading cause, and stroke, when considered separately from CVD, the third. And coronary heart disease alone--even when considered separately from other cardiovascular diseases--was still by far the nation's single leading cause of death (451 326 deaths in 2004).
But while CVD deaths are on the decline, the prevalence of many risk factors is increasing, says the report. Among adults, 66% are now overweight, while 31.4% are obese. Among children and adolescents aged 12 to 19, 17% are overweight (up from 6.1% in 1971–1974), as are 17.5% of six- to 11-year-olds (up from 4.0%). And even in the 2-to-5 age range, 14% of children are overweight.
One-and-a-half million new cases of diabetes were diagnosed in people over the age of 20 in one year, the report adds, and it is projected that diabetes prevalence will more than double from 2005 to 2050.
In addition, the incidence of reported end-stage renal disease has more than doubled in the past 10 years, and the prevalence of chronic kidney disease has increased to 16.8%, from 14.5% in 1988-1994.
Obesity and diabetes: Alarm bells should ring
"Obesity and diabetes are very definitely on the rise," Lloyd-Jones told heartwire. "So any improvements in cardiovascular disease mortality we have seen over past decades are likely to be reversed very soon.
"We are well into this obesity and diabetes epidemic, and we are going to start to pay the price very soon. We need to have the alarm bells fully ringing, and we need to address these issues, which is going to require intensive lifestyle changes as well as more medications, undoubtedly."
As evidence of this, Lloyd-Jones refers to a "beautiful" piece of research published last month in the Journal of the American College of Cardiology [2], which he says they were unable to include in this year-end report. As reported by heartwire, this paper found that mortality rates from coronary heart disease in the US appear to be leveling in young adults and may even be rising.
A major factor in this epidemic is poor diet, with the report showing that fewer than one in three adults in the US eats fruit two more times a day and just under 30% eat vegetables three or more times a day. And smoking--which raises the risk of CHD by two to three times--is still very prevalent, with 46 million Americans still smoking.
The burden of nonfatal events
Also of major concern is the fact that nonfatal events are not declining, adds Lloyd Jones. "These are very important events. These are people who have a heart attack, a major coronary event, or a stroke and are often disabled by that event. They certainly require a lot of medication, a lot of healthcare expenditure, and many require care from family members.
"There are a lot of repercussions of nonfatal events, and these are not really going down. The disability that comes from CVD is a major burden for individuals," he stresses.
On a more positive note, however, the report shows that improvements have been made in the quality of care that cardiovascular disease patients receive in the US. From 2002 through 2004, among almost 160 000 patients treated for heart failure at 285 hospitals, there were improvements in beta-blocker prescriptions, left ventricular assessments, counseling at discharge, and advice on smoking cessation.
Quality of care also improved via the AHA's Get With the Guidelines Program. For coronary artery disease, some key performance measures showed good progress, including whether patients received aspirin, cholesterol-lowering drugs, and other medications and advice on stopping smoking when they were discharged from the hospital. Composite quality-of-care scores for stroke were also improved.
Author disclosures are listed at the end of the report.

Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke statistics--2008 Update. A report from the American Heart Association Statistics Committee and Stroke statistics subcommittee. Circulation 2007; DOI: 10.1161/CIRCULATIONAHA.107.187998. Available at: Abstract
Ford ES, Capewell S. Coronary heart disease mortality among young adults in the US from 1980 through 2002. Concealed leveling of mortality rates. J Am Coll Cardiol 2007; 50:2128-2132. Abstract